Mixed lineage leukemia (MLL) is involved over 70% of pediatric and 10% of adult AML. Treatment with chemotherapy regimens report infant survival rates of about 25-45%, with high relapse rates pre- transplantation being a major contributor of mortality. There is obviously unmet need for more effective therapy. Recent evidence from clinical patient samples as well as studies from mouse model suggest there exist a subgroup of MLL-fusion proteins (MFP), including MLL-AF9 and MLL-ENL, that can activate the Mecom locus, leading to extremely poor prognosis. Using ME knockout mouse model, we have demonstrated that in MFP-induced murine leukemias, knockout of Mecom results in complete loss of viability within 48 hrs. In addition, bone marrow from mice lacking one particular Mecom isoform (termed MDS1-EVI1, or ME) is completely resistant to leukemic transformation by MFPs but not other leukemogenic oncoproteins. Importantly, ME deletion does not result in lethality of normal cells or the organism. Compared to other avenues for therapeutic intervention for MFP, the fact that Mecom activation is linked to extreme poor prognosis in MFP AML, suggest our strategy to target Mecom has significant clinical relevance. The ME protein is distinct from other Mecom isoforms in that it has a PR domain (or MEPRD), related to histone methyltransferases (HMT), which play a critical role in chromatin modification and regulation of gene expression. We have evidence that MEPRD is critical for MFP AMLs. In this application, we propose testing the hypothesis that the ME protein, particularly the MEPRD plays an essential role in MFP AMLs. Through these proposed experiments, we wish to explore these hypotheses that: ME constitutes a downstream target gene of MFPs that is essential for survival, with the PR domain being of critical importance; that ME functions in the nucleus as part of a holocomplex and effecting changes in gene expression of key ROS and apoptosis regulators by modifying chromatin. The results generated from these experiments will help to set up a solid foundation for future small molecule therapeutic development.